Dosage forms of risedronate

ABSTRACT

Oral dosage forms of a risedronate comprised of a safe and effective amount of a pharmaceutical composition comprising risedronate, a chelating agent, and, means for effecting delayed release of the risedronate and the chelating agent in the small intestine provide immediate release of the pharmaceutical composition to the small intestine of the mammal subject and pharmaceutically effective absorption of the bisphosphonate with or without food or beverages. The present invention substantially alleviates the interaction between risedronate and food or beverages, which interaction results in the bisphosphonate active ingredient not being available for absorption. The resulting oral dosage form may thus be taken with or without food. Further, the present invention effects delivery of risedronate and the chelating agent to the small intestine, substantially alleviating the upper GI irritation associated with bisphosphonate therapies. These benefits simplify previously complex treatment regimens and can lead to increased patient compliance with bisphosphonate therapies.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. application Ser. No.11/106,816, filed Apr. 15, 2005 which claims the benefit of ProvisionalApplication Ser. No. 60/573,881, May 24, 2004

FIELD OF THE INVENTION

The present invention relates to oral dosage forms of risedronatecomprised of a safe and effective amount of a pharmaceutical compositioncomprising a bisphosphonate, a chelating agent for enablingadministration of risedronate with food or beverages, means foreffecting delayed release of risedronate and the chelating agent in thesmall intestine, and one or more pharmaceutically-acceptable excipients.The oral dosage forms of the invention provide delivery of thepharmaceutical composition to the small intestine of the mammal subjectand provide pharmaceutically effective absorption of risedronate whenadministered with or without food or beverages. The present inventionfurther relates to a method of treating or preventing diseasescharacterized by abnormal calcium and phosphate metabolism comprisingadministering to a human or other mammal in need thereof the oral dosageform described herein.

BACKGROUND OF THE INVENTION

Bisphosphonates were first developed to complex calcium in hard water toimprove detergent performance. Bisphosphonates have since been found tobe useful in the treatment and prevention of diseases or conditionscharacterized by abnormal calcium and phosphate metabolism. Suchconditions may be divided into two broad categories:

1. Conditions which are characterized by anomalous mobilization ofcalcium and phosphate leading to general or specific bone loss orexcessively high calcium and phosphate levels in the fluids of the body.Such conditions are sometimes referred to herein as pathological hardtissue demineralization.

2. Conditions which cause or result from deposition of calcium andphosphate anomalously in the body. These conditions are sometimesreferred to herein as pathological calcifications.

The first category includes osteoporosis, a condition in which bone hardtissue is lost disproportionately to the development of new hard tissue.Essential quantities of cancellous bone are lost, and marrow and bonespaces become larger, resulting in reduced cancellous bone strength.Bone also becomes less dense and fragile. Osteoporosis can besub-classified as senile, drug induced (e.g., adrenocorticoid, as canoccur in steroid therapy), disease induced (e.g., arthritic and tumor),etc., however the manifestations are similar. Another condition in thefirst category is Paget's disease (osteitis deformans). In this disease,dissolution of normal bone occurs, which is then haphazardly replaced bysoft, poorly mineralized tissue such that the bone becomes deformed frompressures of weight bearing, particularly in the tibia and femur.Hyperparathyroidism, hypercalcemia of malignancy, and osteolytic bonemetastasis are conditions also included in the first category.

The second category, involving conditions manifested by anomalouscalcium and phosphate deposition, includes myositis ossificansprogressiva, calcinosis universalis, and such afflictions as arthritis,neuritis, bursitis, tendonitis, and other inflammatory conditions whichpredispose involved tissue to deposition of calcium phosphates.

Bisphosphonates tend to inhibit the resorption of bone tissue, which isbeneficial to patients suffering from excessive bone loss. However, manyof the early bisphosphonates, such as ethane-1,1-diphosphonic acid(EHDP), propane-3-amino-1-hydroxy-1,1-diphosphonic acid (APD), anddichloromethane diphosphonic acid (Cl₂MDP), have the propensity ofinhibiting bone mineralization when administered at high dosage levels.Although more biologically potent bisphosphonates exist, which can beadministered at lower dosage levels (such as1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid(risedronate), alendronate, ibandronate, and zoledronate), oraladministration of bisphosphonates sometimes results in patientcomplaints shortly after dosing. These complaints are usuallycharacterized by the patients as heartburn, esophageal burning, painand/or difficulty upon swallowing, and/or pain existing behind and/ormid-sternum. It is hypothesized that this irritation results from thebisphosphonate tablet adhering to epithelial and mucosal tissues,resulting in the topical irritation thereof. In order to avoid potentialupper gastrointestinal irritation, patients taking bisphosphonates areinstructed to take their medication with a full glass of water, and toremain upright for at least thirty minutes after taking an oral dose ofa bisphosphonate.

It is known that oral doses of bisphosphonates are poorly absorbed (lessthan 1% of the oral dose) in the gastrointestinal (GI) tract. See Ezraet al., Adv. Drug Del. Rev. 42: 175-95 (2000). Several approaches havebeen suggested for increasing absorption of oral bisphosphonatesthroughout the GI tract. These approaches include modifying thepermeability properties of the intestinal mucosa (e.g., through the useof absorption enhancers), or altering the physical or chemicalproperties of the bisphosphonate compounds themselves (e.g., throughprodrugs).

While the use of absorption enhancers, such asethylenediaminetetraacetic acid (EDTA), that increase intestinalpermeability at high doses, has been proposed as a means of increasingabsorption of oral bisphosphonates, the applicability of EDTA as anagent in human pharmacotherapy has been thought to be “impossible” inlight of the effects of EDTA on mucosal integrity. Ezra et al., Adv.Drug Del. Rev. 42: 185 (2000). Still others have concluded that the highamount of EDTA required to effect an increase in GI absorption wouldexclude the agent as a candidate for use in oral bisphosphonatetherapies. See Janner et al., Calcif. Tissue Int. 49: 280-83 (1991).

While the primary site of bisphosphonate absorption is the smallintestine, bisphosphonates such as risedronate have similar absorptionthroughout the small intestine independent of where it was delivered.See Mitchell et al., Pharm Res., Vol. 15, No. 2: 228-232 (1998). Thustargeted delivery of the bisphosphonate alone to the small intestinewould not increase absorption or efficacy of the bisphosphonate.However, others have attempted to increase the absorption ofbisphosphonates by increasing the permeability of the intestinal mucosathrough delivery of microparticles of chelating agents andbisphosphonate to the reported site of absorption (BR2001-006601).

Bisphosphonates such as risedronate and alendronate have been approvedby a number of regulatory agencies as being effective in the treatmentof various bone pathologies. However, interactions betweenbisphosphonates and foods and minerals (especially cations like calcium,magnesium, aluminum, and iron-containing foods or supplements) causeless of the bisphosphonate to be available for absorption. For example,in Mitchell et. al., Br. J. Clin. Pharmacol. 48: 536-542 (1999), it wasdemonstrated that administration of risedronate within 30 minutes of ameal reduced the amount absorbed by 50% compared to administration inthe fasting state. In order to reduce this food effect, the labeling oforal bisphosphonate products instruct patients to take their medicationat least thirty minutes or in the case of Ibandronate sixty minutes,before the first food of the day, and are instructed to take theircalcium supplements at another time of the day, or on a day when theyare not taking an oral dose of a bisphosphonate. These dosinginstructions can seem complex and inconvenient to the patient, which canlead to poor patient compliance.

There is an ongoing need to develop an oral dosage form of abisphosphonate which can be taken with or without food or beverages(i.e. has pharmaceutically effective absorption regardless of food orbeverage intake), at the preference of the patient, and which does notproduce upper gastrointestinal irritation.

It has been found that a pharmaceutical composition comprisingrisedronate, a sufficient amount of chelating agent to bind the ions andminerals in food, and a means for effecting delayed release ofrisedronate and the chelating agent in the small intestine is useful inproviding an oral dosage form which provides immediate release ofrisedronate to the small intestine, as well as pharmaceuticallyeffective absorption of risedronate when administered with or withoutfood or beverages. The oral dosage forms of the present invention may betaken with or without food or beverages, thus simplifying thebisphosphonate treatment therapy and leading to increased patientcompliance and convenience. Further, the oral dosage forms of theinvention provide for delayed release of risedronate and the chelatingagent in the small intestine, which may alleviate the uppergastrointestinal irritation experienced with other oral bisphosphonatedosage forms and the need to remain upright for thirty minutes post-doseadministration.

SUMMARY OF THE INVENTION

The present invention relates to an oral dosage form of risedronateactive ingredient comprising a safe and effective amount of apharmaceutical composition comprising:

-   -   (a) from about 1 mg to about 250 mg risedronate;    -   (b) from about 10 mg to about 970 mg of a chelating agent; and    -   (c) a delayed release mechanism to immediately release the        risedronate and the chelating agent in the small intestine;        wherein such composition is a tablet size of no greater than one        gram.

The dosage forms of the present invention provide an immediate releaseof risedronate and the chelating agent to the small intestine of themammal subject and pharmaceutically effective absorption of risedronateactive ingredient when administered with or without food or beverages.

The present invention substantially alleviates the interaction betweenrisedronate and food, which interaction results in decreased absorptionof risedronate. The resulting novel oral dosage form may thus be takenwith or without food or beverages, which simplifies previously complextreatment regimens and can lead to increased patient compliance withbisphosphonate therapies and if the patients are compliant their diseasecan be better treated. The invention further alleviates the potentialfor upper gastrointestinal irritation associated with non-delayed,immediate release oral dosage forms of bisphosphonates, by delayingrelease of the bisphosphonate active ingredient until the bisphosphonateand the chelating agent reach the small intestine.

The present invention further relates to a method of treating orpreventing diseases characterized by abnormal calcium and phosphatemetabolism comprising administering to a human or other mammal in needthereof the oral dosage form described herein.

The invention further relates to a kit comprising one or more oraldosage forms of the present invention and means for facilitatingcompliance with methods of this invention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and Usage of Terms

The term “immediate release” as used herein means dissolution of thecore tablet in less than 60 minutes, when measured by standard USPdefinitions. For example, the USP specifies that all tablets andcapsules are subject, to a general dissolution standard of not less than75% of the core content is dissolved in not more than 45 minutes in 900mL of water, using the apparatus, procedures, and interpretationpresented in the United States Pharmacopeia chapter, Dissolution, page959. For this purpose, 75% is Q, and conformance is demonstrated witheither one of Apparatus 1 at 100 rpm or Apparatus 2 at 50 rpm.″

The terms “continuous” or “continuously,” as used herein, mean atregular specified intervals. For example, a continuous scheduleaccording to a dosing regimen of once weekly means that the active isgiven one time per week for an unspecified period of time or for as longas treatment is necessary.

The term “delayed release or delayed delivery,” as used herein, refersto formulating the pharmaceutical composition comprising risedronate andthe chelating agent so that their release will be accomplished at somegenerally predictable location in the small intestine.

The term “nutrient,” as used herein, means any nutritional or dietarysupplement including but not limited to vitamins, minerals, amino acids,herbs or other botanicals, or concentrates, metabolites, constituents,extracts, or combinations of the same.

The term “pharmaceutical composition,” as used herein, means an oraldosage form comprised of a safe and effective amount of risedronate andone or more pharmaceutically-acceptable excipients including at leastone chelating agent. The pharmaceutical compositions described hereinare comprised of from 0.5% to 75%, preferably from 1% to 40% ofrisedronate and from 25% to 99.5%, preferably from 60% to 99% ofpharmaceutically-acceptable excipients including at least one chelatingagent.

The term “safe and effective amount,” as used herein, means an amount ofa compound or composition high enough to significantly positively modifythe symptoms and/or condition to be treated, but low enough to avoidserious side effects (at a reasonable risk/benefit ratio), within thescope of sound medical judgment. The safe and effective amount of activeingredient for use in the method of the invention herein will vary withthe particular condition being treated, the age and physical conditionof the patient to be treated, the severity of the condition, theduration of the treatment, the nature of concurrent therapy, theparticular active ingredient being employed, the particularpharmaceutically-acceptable excipients utilized, and like factors withinthe knowledge and expertise of the attending physician.

The term “pharmaceutically effective absorption” as used herein means anamount of a chelating compound high enough to significantly bind themetal ions and minerals in food but low enough not to significantlyalter absorption of risedronate as compared to absorption in the fastedstate. That is, absorption is similar with or without food. Given thehigh variability of bisphosphonate absorption, fed exposure within about50% of fasting exposure is expected to be pharmaceutically effectiveabsorption.

The term “oral dosage form,” as used herein, means any pharmaceuticalcomposition intended to be delivered or released to the small intestineof a human or other mammal via the mouth of said human or other mammal.For the purposes of the present invention, the delivered form can be inthe form of a compressed tablet containing granules or particles ofrisedronate and a chelating agent

The term “unit dose” or “unit dosage” means a dosage form containing anamount of pharmaceutical active or nutrient suitable for administrationin one single dose, according to sound medical practice. The presentinvention is particularly useful for the administration of unit doses inthe form of tablets and capsules.

The term “gastrointestinal tract” or “GI tract,” as used herein, relatesto the alimentary canal, i.e., the musculo-membranous tube about thirtyfeet in length, extending from the mouth to the anus. The term “uppergastrointestinal tract,” as used herein, means the buccal cavity, thepharynx, the esophagus, and the stomach. The term “lowergastrointestinal tract,” as used herein, means the small intestine andthe large intestine.

The term “small intestine,” as used herein, means the part of the smallintestine consisting of just distal to the stomach, including theduodenum, the jejunum, and the ileum, i.e., that portion of theintestinal tract just distal to the duodenal sphincter of the fundus ofthe stomach and proximal to the large intestine. The term “largeintestine,” as used herein, means the part of the lower gastrointestinaltract including the ascending colon, the transverse colon, thedescending colon, the sigmoid colon, and the rectum

Risedronate

The terms “bisphosphonate” and “diphosphonate,” as used herein, includeacids, salts, esters, hydrates, polymorphs, hemihydrates, solvates, andderivatives thereof. The bisphosphonates of the present inventioninclude those forms of1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid(risedronate) as described in U.S. Pat. No. 5,583,122, to Benedict etal., issued Dec. 10, 1996; U.S. Pat. No. 6,410,520 B2, to Cazer et al.,issued Jun. 25, 2002

Non-limiting examples of salts useful herein include those selected fromthe group consisting of alkali metal, alkaline metal, ammonium, andmono-, di-, tri-, or tetra-C₁-C₃₀-alkyl-substituted ammonium. Preferredsalts are those selected from the group consisting of sodium, potassium,and ammonium salts.

The amount of risedronate contained in the oral dosage forms of thepresent invention will depend on the particular risedronate formselected and the continuous dosing schedule upon which the risedronateis dosed to the patient. Continuous dosing schedules of daily, weekly,twice monthly, three times per month, and once monthly are non-limitingexamples of dosing regimens suitable for use with the oral dosage formsof the present invention. The terms “three times per month” or “thricemonthly” mean that an oral dosage form is administered thrice, i.e.,three times, during a monthly calendar period. In a thrice monthlyschedule, the oral dosage forms may be administered on three consecutivedays, or once about every nine to eleven days. The terms “twice permonth” or “twice monthly” mean that an oral dosage form is administeredtwice, i.e., two times, during a monthly calendar period. In a twicemonthly regimen, the oral dosage forms may be administered onconsecutive days or once about every fourteen to sixteen days. The terms“monthly” or “once monthly” mean that an oral dosage form isadministered once, i.e., one time during a monthly calendar period, thatis, about every 28 to 31 days.

Mixed nomenclature is currently in use by those of ordinary skill in theart, for example reference to a specific weight or percentage of abisphosphonate active ingredient is on an anhydrous monosodium saltbasis for risedronate. For the present invention, the phrase “about 35mg of risedronate, pharmaceutically acceptable salts thereof, andmixtures thereof, on an anhydrous monosodium salt basis” means that theamount of the risedronate compound selected is calculated based on about35 mg of anhydrous risedronate monosodium salt.

Generally, the oral dosage forms of the present invention will containfrom about 1 mg to about 250 mg of risedronate on a risedronateanhydrous monosodium salt basis. A daily oral dosage form of the presentinvention contains from about 1 mg to about 10 mg risedronate on arisedronate anhydrous monosodium salt basis. A weekly oral dosage formcontains from about 10 to about 70 mg risedronate on a risedronateanhydrous monosodium salt basis, preferably from 15 to about 55 mgrisedronate, more preferably from about 35 mg to about 50 mgrisedronate. A twice monthly oral dosage form contains from about 20 toabout 120 mg risedronate, preferably about 75 mg to about 90 mgrisedronate on a risedronate anhydrous monosodium salt basis. An oraldosage form that is administered three times per month contains fromabout 15 to about 90 mg risedronate, preferably about 50 mg to about 75mg risedronate, on a risedronate anhydrous monosodium salt basis. Amonthly oral dosage form contains from about 50 to about 280 mgrisedronate, preferably from about 100 to about 250 mg risedronate, andmore preferably about 150 to about 200 mg risedronate on a risedronateanhydrous monosodium salt basis. In one embodiment of the invention thedosage form contains about 100% of the effective amount of therisedronate as equivalent non-chelating agent containing, non-delayed,immediate released risedronate tablets. In yet another embodiment of theinvention the dosage form is about 145% of the effective amount of therisedronate as equivalent non-chelating agent containing, non-delayed,immediate released risedronate tablets.

Chelating Agent

The term “chelating agent,” as used herein, means a molecule containingtwo or more electron donor atoms that can form coordinate bonds to asingle metal ion. The term “chelating agent” is understood to includethe chelating agent as well as salts thereof. For example, the term“chelating agent” includes citric acid as well as its salt forms.

The most common and widely used chelating agents coordinate to metalatoms through oxygen or nitrogen donor atoms, or both. Other less commonchelating agents coordinate through sulfur in the form of —SH (thiol ormercapto) groups. After the first coordinate bond is formed, eachsuccessive donor atom that binds creates a ring containing the metalatom. A chelating agent may be bidentate, tridentate, tetradentate,etc., depending upon whether it contains two, three, four, or more donoratoms capable of binding to the metal atom. See Kirk-Othmer Encyclopediaof Chemical Technology (4th ed. 2001).

In homogeneous dilute solutions, the equilibrium constant for theformation of the complex from the solvated metal ion (e.g., calcium) andthe chelating agent in its fully dissociated form is called theformation or stability constant, K. The practical significance offormation constants is that a high log K value means a large ratio ofchelated to unchelated (or free) metal ion, when equivalent amounts ofmetal ion and chelating agent are present. Higher ratios (or differenceif K is expressed in log units) of the chelating agent and thebisphosphonate complexation constants are preferred in order to havenearly all of the metal ion complexed to the chelating agent instead ofthe bisphosphonate. For example, for equal molar amounts of bothbisphosphonate and the chelating agent, in order for the metal ions tobe 99% complexed to the chelating agent, the chelating agent must have alog K which is at least 4 units higher than the bisphosphonate-metal ioncomplex. The other technique which can be used to favor the chelatingagent-metal ion complex over that of the bisphosphonate-metal ioncomplex is to add a molar excess of the chelating agent which relies onthe law of mass action to favor formation of the chelating agent-metalion complex.

Although pH and solution concentration can affect the formationconstant, in general, the log K of the chelating agent is preferably atleast equal to that of the bisphosphonate. In other instances the log Kof the chelating agent is 2 to 5 units higher than that of thebisphosphonate. In other instances, the chelating agent is present at amolar excess to that of the bisphosphonate. The chelating agent in suchinstances is present in at least a 2:1 molar ratio of the chelatingagent to bisphosphonate.

The chelating agent and the form it is administered is at least 50% assoluble in water as risedronate. In other instances the chelating agentand the form it is administered may have a solubility comparable to orgreater than that of risedronate.

In one embodiment, the chelating agent is selected from the groupconsisting of sodium or disodium EDTA, citric acid, malic acid, tartaricacid, lactic acid, adipic acid, succinic acid, lysine, sodiumhexametaphosphate, and combinations thereof. In another embodiment, thechelating agent is sodium of disodium EDTA, citric acid, or sodiumhexametaphosphate.

The amount of chelating agent present in the oral dosage form of thepresent invention will depend on the particular chelating agent oragents (i.e. mixtures of chelating agents) selected, the amount ofbisphosphonate active ingredient present in the oral dosage form, andthe specific portion of the small intestine where delivery and releaseof the chelating agent and/or bisphosphonate active ingredient isdesired. After the ingestion of milk, it has been shown in the art thatthe concentration of calcium decreases over the length of the lower GItract, beginning with the small intestine and proceeding through to theend of the small intestine. Mahe, J. et al., Gastroileal nitrogen andelectrolyte movements after bovine milk ingestion in humans, Am. J.Clin. Nutr. 56: 410-16 (1992).

The concentration of calcium in the stomach is approximately 10-foldhigher than that of the concentration in the jejunum and approximately40 times that in the ileum. Thus, if the risedronate and chelating agentwere released in the stomach (with food), the amount of chelating agentof the present invention would be insufficient to overcome the effect ofcalcium on drug absorption. The concentration of calcium in the jejunumand ileum are lower and by targeting release of the dosage form in theseregions where the amount of calcium is lower, the chelating agent ismore effective at binding most of all of the calcium than if released inthe stomach. It is also desirable not only to have targeted release ofthe tablet in the small intestine but after the coating dissolves thechelating agent and risedronate from the core tablet releases in animmediate release fashion. This maximizes the local concentration of thechelating agent in relationship to that of the calcium in the smallintestine. Slow or prolonged delivery of the chelating agent in thesmall intestine does not achieve the desired local concentration of thechelating agent and this type of delivery will not overcome the foodeffect.

Generally, the oral dosage forms of the present invention will contain asafe and effective amount of a chelating agent suitable for achievingthe desired chelating effect, that is, chelating the residual metal ionsthat are present in the gastrointestinal tract from food at the site ofdelivery without significantly affecting the absorption of thebisphosphonate had no food been present. In one embodiment, the oraldosage form contains from about 10 mg to about 1000 mg of a chelatingagent per unit dose. In another embodiment, the oral dosage formscontain from about 10 mg to about 500 mg of a chelating agent per unitdose. When the chelating agent is disodium EDTA, the preferred range isfrom about 55 mg to about 500 mg, preferably from about 75 mg to about250 mg per unit dose. When the chelating agent is citric acid, thepreferred range is from about 100 mg to about 970 mg, preferably fromabout 250 mg to about 500 mg per unit dose.

Delayed Delivery to the Small Intestine

The ultimate site of and/or the rate of delivery in the small intestinecan be satisfactorily controlled by one skilled in the art, bymanipulating any one or more of the following:

-   -   (a) the active ingredient proper;    -   (b) the type and level of disintegrant;    -   (c) the type of coating, the type and level of excipients added        to the coating and the concomitant desirable thickness and        permeability (swelling properties) of the coating;    -   (d) the time dependent conditions of the coating itself and/or        within the coated tablet, particle, bead, or granule;    -   (e) the particle size of the granulated active ingredient;    -   (f) the pH dependent conditions of the coating itself and/or        within the coated tablet, particle, bead, or granule;    -   (g) the particle size or solubility of the chelating agent;    -   (h) the dissolution rate of the coating;    -   (i) size or shape of the tablet.

In addition the pharmacodynamic effect of the tablets, after multipledosing, should be within at least 75% of the comparable immediaterelease tablet.

Delayed Release in the Small Intestine

A human or other mammal suffering from diseases or disorders involvingcalcium and phosphate metabolism can be successfully treated by thedelivery of risedronate to the small intestine of said human or othermammal. The novel dosage forms described herein effect an immediaterelease to the small intestine, and prohibit the undesired release ofrisedronate in the mouth, pharynx, esophagus, and/or stomach, therebyprohibiting the erosion, ulceration, or other like irritation of theepithelial or mucosal layers of these tissues.

The chelant and risedronate are released rapidly and as close tosimultaneously as possible. This causes the local concentration ofchelating agent to be higher in relationship to the metal ions in thefood. The higher local concentration of chelating agent in theenvironment where the active is released may more effectively complexthe metals in the food and facilitate absorption of the bisphosphonate.This can be conveniently achieved from a single tablet.

Various means for targeting release of risedronate and the chelatingagent in the small intestine are suitable for use in the presentinvention. Non-limiting examples of means for delivery to the smallintestine include pH triggered delivery systems and time dependentdelivery systems.

pH Triggered Delivery Systems

One embodiment of the present invention involves coating (or otherwiseencapsulating) the risedronate and the chelating agent(s) with asubstance which is not broken down, by the gastrointestinal fluids torelease the risedronate and the chelating agent until a specific desiredpoint in the intestinal tract is reached. In one embodiment, delayedrelease of the pharmaceutical composition is achieved by coating thetablet, capsule, particles, or granules, of the risedronate and thechelating agent with a substance which is pH dependent, i.e., brokendown or dissolves at a pH which is generally present in the smallintestine, but not present in the upper GI tract (i.e., the mouth,buccal cavity, pharynx, esophagus, or stomach) or lower GI tract.

In some cases, it may be desirable that the risedronate and thechelating agent are released at a particular location in the smallintestine. In other cases, it may be desirable to release therisedronate and the chelating agent independently at different locationswithin the small intestine. For example, it may be desirable to releasethe chelating agent in the, jenunum and the risedronate in the.ileumWhen targeted release of the risedronate and the chelating agenttogether or separately in particular locations within the smallintestine is desired, the selection of the coating material and/or themethod of coating or otherwise combining the risedronate and thechelating agent with the selected coating material or otherpharmaceutically-acceptable excipients may be varied or altered as isdescribed herein, or by any method known to one skilled in the art.

Solubility, acidity, and susceptibility to hydrolysis of the differentrisedronate active ingredients, such as acid addition salts, saltsformed with the phosphonic group (e.g., alkali metal salts, alkalineearth metal salts, etc.), and esters (e.g., alkyl, alkenyl, aryl,arylalkyl) may be used as guidelines for the proper choice of coating.In addition, suitable pH conditions might be established within thecoated tablets, particles, or granules by adding a suitable buffer tothe active ingredient in accordance with the desired release pattern.

One embodiment of the present invention is delivered to the smallintestine utilizing a pH dependent enteric coating material made from apartly methyl esterified methacrylic acid polymer. The oral dosage formcan be in the form of an enteric coated compressed tablet made ofgranules or particles of active ingredient.

Any enteric coating which is insoluble at a pH below 5.5 (i.e., thatgenerally found in the mouth, pharynx, esophagus, and stomach), butsoluble between about pH 5.5 and about pH 6.5 (i.e., that present in thesmall intestine) can be used in the practice of the present invention.Accordingly, when it is desired to effect delivery of the bisphosphonateand the chelating agent to the small intestine, any enteric coating issuitable which is wholly- or partially-insoluble at a pH below 5.5 andsoluble at about a pH 5.5 to about pH 6.5.

The enteric coating must be applied to the compressed tablet, or capsule(e.g., gelatin, starch, or hydroxypropylmethylcellulose) in a sufficientthickness so that the entire coating does not dissolve ingastrointestinal fluids at a pH below 5.5, but does dissolve at a pHabove about 5.5 and below pH about 6.5. The dissolution ordisintegration of the excipient coating generally does not occur untilthe entry of the coated dosage form into the small intestine.

It is expected that any anionic polymer exhibiting the requisitepH-dependent solubility profile can be used as an enteric coating in thepractice of the present invention to achieve delivery of thebisphosphonate and chelating agent to the small intestine. The coatingchosen must be compatible with the particular risedronate activeingredient selected. The preferred polymers for use in the presentinvention are anionic carboxylic polymers. It is particularly preferredthat the polymers are acrylic polymers, more preferably partlymethyl-esterified methacrylic acid polymers, in which the ratio of freeanionic carboxyl groups to ester groups is about 1:1

A particularly suitable methacrylic acid copolymer is Eudragit L®,particularly Eudragit L 30 D-55® and Eudragit L 100-55®, manufactured byRöhm Pharma GmbH and Co. KG, Darmstadt, Germany. In Eudragit L 30 D-55®,the ratio of free carboxyl groups to ester groups is approximately 1:1.Further, said copolymer is known to be insoluble in GI fluids having apH below 5.5, generally 1.5-5.5, i.e., that generally present in thefluid of the upper GI tract, but readily soluble at pH above 5.5, i.e.,that generally present in the fluid of the small intestine.

The coating can, and usually will, contain a plasticizer and possiblyother coating excipients such as coloring agents, surfactant, talc,and/or magnesium stearate, many of which are well known in the coatingart. In particular, anionic carboxylic acrylic polymers usually willcontain 10-25% by weight of a plasticizer, especially triethyl citrate,tributyl citrate, acteyltriethyl citrate, dibutyl phthalate, diethylphthalate, polyethylene glycol, acetylated monoglycerides propyleneglycol, and triacetin. Conventional coating techniques such as fluid-bedor pan coating are employed to apply the coating. Coating thickness mustbe sufficient to ensure that the oral dosage form remains essentiallyintact until the desired site of delivery in the small intestine isreached.

The solid oral dosage form may be in the form of a coated compressedtablet which contains particles or granules of the bisphosphonate activeingredient and the chelating agent, or of a soft or hard capsule (e.g.,gelatin, starch, or hydroxypropylmethylcellulose), coated or uncoated,which contains beads or particles of the bisphosphonate activeingredient and the chelating agent, which themselves are entericallycoated. In an embodiment of the invention the tablets are compressed andthe tablet is enteric coated.

Suitable enteric coating materials include Eudragit L-100®, Eudragit L30 D-55®, cellulose acetate phthalate, shellac, or any enteric coatingmaterial that dissolves at about pH 5.5 to about 6.5. The entericcoating is applied using various spray techniques known to one skilledin the art. The enteric coating may further comprise one or morepharmaceutically-acceptable excipients including, but not limited to,talc, triethyl citrate, polyethylene glycol, Tween 80® (polyoxyethylenesorbitan monooleate, available from Sigma Chemical CO., St. Louis, Mo.),castor oil. The enteric coating is applied to the tablet core to providea weight gain of 2.5% to 40%.

The tablet core comprises a bisphosphonate active ingredient, achelating agent, and may contain one or more pharmaceutically-acceptableexcipients. Suitable excipients include, but are not limited to,crystalline cellulose, lactose, calcium hydrogen phosphate,polyvinylpyrrolidone, magnesium stearate, sucrose, starch, magnesiumoxide, sodium starch glycolate and sodium lauryl sulfate.

Time Dependent Delivery Systems

In another embodiment of the invention, delivery of the risedronate andthe chelating agent to the small intestine is achieved through the useof a time dependent delivery system. Given established transit timesafter gastric emptying, drug and/or chelating agent release can betargeted to the various segments of the small intestine. Approaches totime dependent delivery systems suitable for use in the presentinvention include, but are not limited to, such devices as thePulsincap™ (Scherer DDS, Strathclyde, U.K.), the Time Clock™ (ZambonGroup, Milan, Italy), and SyncroDose™ (Penwest, Patterson, N.Y.), aswell as various coatings which degrade over time to release tabletcontents such as hydroxypropylmethylcellulose, hydroxypropylcellulose,or any suitable hydrogel.

In one embodiment of the invention, the time-dependent device Pulsincap™is used to target delivery of the active ingredient and the chelatingagent to the small intestine. The active ingredient and otherexcipients, including the chelating agent, are contained inside thePulsincap™ water-insoluble capsule by means of a hydrogel plug which iscovered by a water-soluble cap. The entire dose form is optionallycoated in an enteric-coating material to protect the dose form fromdegradation while in transit through the upper GI tract. When thepatient swallows the Pulsincap™ dosage form, the water-soluble capdissolves and exposes the hydrogel plug to gastric and/or intestinalfluids. The hydrogel cap then swells, and eventually pops out of thecapsule body, thus releasing the capsule contents. Release of thecapsule contents can be targeted to specific regions of the smallintestine by modifying the hydrogel plug properties. Watts, Peter J. &Illum, Lisbeth, Drug Dev. and Indus. Pharm., 23(9): 893-917 (1997).

In one embodiment of the invention, a time dependent coating is appliedover a compressed tablet and then an enteric coating is applied over thetime dependent coating. This is used to target delivery of the activeingredient and the chelating agent to the small intestine. The activeingredient and other excipients, including the chelating agent, arecontained inside the core tablet. The entire dose form is coated with atime dependent coating and then an enteric coating. The enteric-coatingmaterial is to protect the dose form from degradation while in transitthrough the upper GI tract. When the patient swallows the dosage formthe enteric coating dissolves after the dosage form leaves the stomachand then the core tablet starts to swell. Eventually, at a predeterminedtime in the small intestine fluids, the time dependent coating willrupture and releases the contents of the core tablet in the smallintestine. Release of the core tablet contents can be targeted tospecific regions of the small intestine by modifying the core tablet,time dependent coating and/or the enteric coating.

Pharmaceutically-acceptable Excipients

Pharmaceutically-acceptable excipients include, but are not limited to,polymers, resins, plasticizers, fillers, lubricants, diluents, binders,disintegrants, solvents, co-solvents, surfactants, buffer systems,preservatives, sweetener agents, flavoring agents, pharmaceutical-gradedyes or pigments, chelating agents, viscosity agents, and combinationsthereof. Pharmaceutically-acceptable excipients can be used in anycomponent in making the oral dosage form, i.e. core tablet or coating.

Flavoring agents and dyes and pigments among those useful herein includebut are not limited to those described in Handbook of PharmaceuticalExcipients (4th Ed., Pharmaceutical Press 2003).

Suitable co-solvents include, but are not limited to, ethanol,isopropanol, and acetone.

Suitable surfactants include, but are not limited to, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene monoalkyl ethers, sucrosemonoesters, simethicone emulsion, sodium lauryl sulfate, Tween 80®, andlanolin esters and ethers.

Suitable preservatives include, but are not limited to, phenol, alkylesters of parahydroxybenzoic acid, benzoic acid and the salts thereof,boric acid and the salts thereof, sorbic acid and the salts thereof,chlorbutanol, benzyl alcohol, thimerosal, phenylmercuric acetate andnitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride,methyl paraben, and propyl paraben.

Suitable fillers include, but are not limited to, starch, lactose,sucrose, maltodextrin, and microcrystalline cellulose.

Suitable plasticizers include, but are not limited to, triethyl citrate,polyethylene glycol, propylene glycol, dibutyl phthalate, castor oil,acetylated monoglycerides, and triacetin.

Suitable polymers include, but are not limited to, ethylcellulose,cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate,cellulose acetate phthalate, polyvinyl acetate phthalate, and Eudragit®L 30-D, Eudragit® L 100-55, (Röhm Pharma GmbH and Co. KG, Darmstadt,Germany), and Acryl-EZE® and Sureteric® (Colorcon, Inc., West Point,Pa.).

Suitable lubricants include, but are not limited to, magnesium stearate,stearic acid, and talc.

Methods of Use

The present invention further relates to a method of treating orpreventing diseases characterized by abnormal calcium and phosphatemetabolism comprising administering to a human or other mammal in needthereof a safe and effective amount of a pharmaceutical compositiondelivered to said human or other mammal via the oral dosage formsdescribed herein.

Diseases characterized by abnormal calcium and phosphate metabolisminclude, but are not limited to, osteoporosis, Paget's disease (osteitisdeformans), hyperparathyroidism, hypercalcemia of malignancy, osteolyticbone metastasis, myositis ossificans progressiva, calcinosisuniversalis, and such afflictions as arthritis, neuritis, bursitis,tendonitis, and other inflammatory conditions which predispose involvedtissue to deposition of calcium phosphates.

The oral dosage forms of the present invention are suitable foradministration to a patient according to a continuous dosing interval ofdaily, weekly, three times per month, twice monthly, and monthly.

Kits

The present invention further comprises kits that are particularlyuseful for administering the oral dosage forms described hereinaccording to a continuous dosing schedule of daily, weekly, three timesper month, twice monthly, or monthly. Such kits comprise one or moreoral dosage forms comprising risedronate and a chelating agent and ameans for facilitating compliance with methods of this invention. Suchkits provide a convenient and effective means for assuring that thesubject to be treated takes the appropriate oral dosage form in thecorrect dosage and in the correct manner. The compliance means of suchkits includes any means which facilitates administering the activeaccording to a method of this invention. Such compliance means includesinstructions, packaging, and dispensing means, and combinations thereof.The kits can also comprise a means for aiding the memory, including butnot limited to a listing of the days of the week, numbering,illustrations, arrows, Braille, calendar stickers, reminder cards, orother means specifically selected by the patient. Examples of packagingand dispensing means are well known in the art, including thosedescribed in U.S. Pat. No. 4,761,406, Flora et al., issued Aug. 2, 1988;and U.S. Pat. No. 4,812,311, Uchtman, issued Mar. 14, 1989.

Optionally, the kits can comprise at least one oral dosage formcomprising a risedronate and a chelating agent and at least one oraldosage form of an accompanying nutrient. Preferred nutrients are calciumand/or vitamin D. Oral forms of calcium suitable for use in the presentinvention include capsules, compressed tablets, chewable tablets, andthe like. Typical salt forms of calcium suitable for use in the presentinvention include but are not limited to calcium carbonate, calciumcitrate, calcium malate, calcium citrate malate, calcium glubionate,calcium gluceptate, calcium gluconate, calcium lactate, dibasic calciumphosphate, and tribasic calcium phosphate. In one embodiment, kits ofthe present invention may include tablets comprising 400 mg to 1500 mgcalcium.

The term “vitamin D,” as used herein, refers to any form of vitamin Dthat may be administered to a mammal as a nutrient. Vitamin D ismetabolized in the body to provide what is often referred to as“activated” forms of vitamin D. The term “vitamin D” can includeactivated and non-activated forms of vitamin D, as well as precursorsand metabolites of such forms. Precursors of these activated formsinclude vitamin D₂ (ergocalciferol, produced in plants) and vitamin D₃(cholecalciferol, produced in skin and found in animal sources and usedto fortify foods). Vitamins D₂ and D₃ have similar biological efficacyin humans. Non-activated metabolites of vitamins D₂ and D₃ includehydroxylated forms of vitamins D₂ and D₃. Activated vitamin D analogscannot be administered in large doses on an intermittent schedule, dueto their toxicity in mammals. However, non-activated vitamin D₂, vitaminD₃, and their metabolites may be administered in larger doses than“active” forms of vitamin D on an intermittent basis, without toxicity.In one embodiment, kits of the present invention may include tabletscomprising 100 IU to 10,000 IU of vitamin D.

In another embodiment, kits of the present invention may include one ormore nutrient tablets comprising both calcium and vitamin D. In afurther embodiment, the unit dose of nutrient comprises about 600 mgcalcium and about 400 IU vitamin D.

The following non-limiting examples illustrate the formulations,processes, and uses of the present invention.

EXAMPLES Example I Enteric-Coated Tablets Containing Risedronate andEDTA

Enteric-coated tablets containing risedronate and EDTA are made bypreparing a coating composition and compressed tablets containingrisedronate and EDTA, and then applying said coating composition to saidtablets.

An enteric coating composition is prepared in the form of a lacquercontaining the following excipients, per tablet:

A. Enteric Coating Suspension

Ingredients: Eudragit L 30 D-55 ® (wet basis) 143.3 mg  (manufactured byRöhm Pharma GmbH and Co. KG, Darmstadt, Germany) Triethylcitrate 6.45 mgTalc 21.5 mg Red Iron Oxide 0.22 mg Simethicone emulsion (30%) 0.43 mgPolysorbate 80 0.43 mg Purified Water 307.7 mg 

The enteric coating is prepared using the following method:

A pigment suspension is prepared by adding polysorbate 80, ground ferricoxide, and talc to approximately two-thirds of the purified water whilemixing. The suspension is mixed for at least two hours. The 30%simethicone emulsion and the remaining water are added to the pigmentsuspension and mixed for at least 45 minutes. The Eudragit L 30 D-55solution and triethyl citrate are combined and mixed for at least 45minutes. The pigment suspension is then added to the Eudragit solutionand mixed for 30 to 60 minutes. The resulting coating suspension isscreened and mixed throughout the coating process. The core tablets aretransferred to the coating pan and preheated with occasional jogging.Tablets are coated, using a typical pan coating process until therequired quantity of coating solution has been applied. Tablets are thencooled and collected in suitable containers.

A coating weight gain of 30% (total solids) is applied by spraying theabove composition onto compressed tablets containing risedronate andEDTA, prepared in Part B below.

B. Compressed Tablets Containing Risedronate and EDTA

The enteric coating suspension prepared in Part A above is sprayed onto35 mg risedronate tablets, each tablet weighing 240 mg and eachcontaining:

Active Ingredients: Risedronate Sodium   35 mg* Chelant: Disodium EDTA 100 mg Excipients Microcrystalline cellulose 85.8 mg Sodium starchglycolate   6 mg Stearic acid   12 mg Magnesium stearate  1.2 mg *Thisamount is calculated on a risedronate anhydrous monosodium salt basis.

Tablets having the composition set forth above are prepared as follows:

The risedronate sodium, edetate disodium, sodium starch glycolate, andmicrocrystalline cellulose are passed through a mill and added to ablender equipped with an intensifier bar. The mixture is blended forapproximately ten minutes with the intensifier bar on. The stearic acidand magnesium stearate are screened and added to the blender. The blendis mixed for approximately 3 minutes with the intensifier bar off. Theblend is compressed into tablets using a suitable tablet press.

Example II Enteric-Coated Tablets Containing Risedronate and EDTA

Enteric-coated tablets containing risedronate sodium are prepared asdescribed below, using a similar method set forth in Example I.

A coating composition is prepared from a lacquer containing thefollowing excipients, per tablet:

Ingredients: Acryl-EZE (manufactured by 200 mg Colorcon, Inc., WestPoint, Pa.) dry solids Purified Water 950 mg

A coating weight of 40% weight gain is applied by conventional pancoating to tablets containing 150 mg risedronate and 75 mg EDTA so thatoval tablets, each weighing 500 mg, result. The composition of eachtablet is as follows:

Active Ingredients: Risedronate Sodium  150 mg* Chelant: Disodium EDTA 75 mg Excipients Mannitol 100 mg Starch 1500 159 mg Silicon Dioxide  1mg Stearic acid  15 mg *This amount is calculated on a risedronateanhydrous monosodium salt basis.

Example III Enteric-Coated Tablets Containing Risedronate and EDTA

Enteric-coated tablets containing risedronate and EDTA are made bypreparing a coating composition and compressed tablets containingrisedronate and EDTA, and then applying said coating composition to saidtablets.

An enteric coating composition is prepared in the form of a lacquercontaining the following excipients, per tablet:

A. Enteric Coating Suspension

Ingredients: Eudragit L 30 D-55 ® (wet basis) 51.37 mg  (manufactured byRöhm Pharma GmbH and Co. KG, Darmstadt, Germany) Triethylcitrate 1.54 mgTalc 11.56 mg  Red Iron Oxide 0.02 mg Simethicone emulsion (30%) 0.05 mgPolysorbate 80 0.15 mg Purified Water 79.21 mg 

The enteric coating is prepared using the following method:

A pigment suspension is prepared by adding polysorbate 80, ground ferricoxide, and talc to approximately two-thirds of the purified water whilemixing. The suspension is mixed for at least two hours. The 30%simethicone emulsion and the remaining water are added to the pigmentsuspension and mixed for at least 45 minutes. The Eudragit L 30 D-55solution and triethyl citrate are combined and mixed for at least 45minutes. The pigment suspension is then added to the Eudragit solutionand mixed for 30 to 60 minutes. The resulting coating suspension isscreened and mixed throughout the coating process. The core tablets aretransferred to the coating pan and preheated with occasional jogging.Tablets are coated, using a typical pan coating process until therequired quantity of coating solution has been applied. Tablets are thencooled and collected in suitable containers.

A coating weight gain of approximately 10% (total solids) is applied byspraying the above composition onto compressed tablets containingrisedronate and EDTA, prepared in Part B below.

B. Compressed Tablets Containing Risedronate and EDTA

The enteric coating suspension prepared in Part A above is sprayed onto35 mg risedronate tablets, each tablet weighing 290 mg and eachcontaining:

Active Ingredients: Risedronate Sodium 35 mg* Chelant: Disodium EDTA 100mg Excipients: ProSolv SMCC 90 131.8 mg Stearic Acid 14.5 mg SodiumStarch Glycolate 7.25 Magnesium stearate 1.5 mg *This amount iscalculated on a risedronate anhydrous monosodium salt basis.

Tablets having the composition set forth above are prepared as follows:

The risedronate sodium, edetate disodium, sodium starch glycolate, ½ ofthe ProSolv SMCC90, ½ of the stearic acid and ½ of the magnesiumstearate are passed through a mill and added to a blender equipped withan intensifier bar. The mixture is blended for approximately twentyminutes with the intensifier bar on and then chilsonated and milled. Theremaining ProSolv SMCC90, and stearic acid are added and mixed foranother 10 minutes. The remaining magnesium stearate is screened andadded to the blender with the granulation. The blend is mixed forapproximately 3 minutes with the intensifier bar off. The blend iscompressed into tablets using a suitable tablet press.

Example IV Enteric-Coated Tablets Containing Risedronate and EDTA

Enteric-coated tablets containing risedronate and EDTA are made bypreparing a coating composition and compressed tablets containingrisedronate and EDTA, and then applying said coating composition to saidtablets.

An enteric coating composition is prepared in the form of a lacquercontaining the following excipients, per tablet:

A. Enteric Coating Suspension

Ingredients: Eudragit L 30 D-55 ® (wet basis) 66.10 mg (manufactured byRöhm Pharma GmbH and Co. KG, Darmstadt, Germany) Triethylcitrate 1.99 mgTalc 14.87 mg Yellow Iron Oxide 0.02 mg White Chromatone 0.07Simethicone emulsion (30%) 0.06 mg Polysorbate 80 0.20 mg Purified Water101.89 mg

The enteric coating is prepared using the following method:

A pigment suspension is prepared by adding polysorbate 80, ground ferricoxide, White Chromatone, and talc to approximately two-thirds of thepurified water while mixing. The suspension is mixed for at least twohours. The 30% simethicone emulsion and the remaining water are added tothe pigment suspension and mixed for at least 45 minutes. The Eudragit L30 D-55 solution and triethyl citrate are combined and mixed for atleast 45 minutes. The pigment suspension is then added to the Eudragitsolution and mixed for 30 to 60 minutes. The resulting coatingsuspension is screened and mixed throughout the coating process. Thecore tablets are transferred to the coating pan and preheated withoccasional jogging. Tablets are coated, using a typical pan coatingprocess until the required quantity of coating solution has beenapplied. Tablets are then cooled and collected in suitable containers.

A coating weight gain of approximately 9% (total solids) is applied byspraying the above composition onto compressed tablets containingrisedronate and EDTA, prepared in Part B below.

B. Compressed Tablets Containing Risedronate and EDTA

The enteric coating suspension prepared in Part A above is sprayed onto50 mg risedronate tablets, each tablet weighing 414.3 mg and eachcontaining:

Active Ingredients: Risedronate Sodium 50 mg* Chelant: Disodium EDTA142.9 mg Excipients: ProSolv SMCC 90 188.3 mg Stearic Acid 20.7 mgSodium Starch Glycolate 10.4 Magnesium stearate 2.0 mg *This amount iscalculated on a risedronate anhydrous monosodium salt basis.

Tablets having the composition set forth above are prepared as follows:

The risedronate sodium, edetate disodium, sodium starch glycolate, ½ ofthe ProSolv SMCC90, ½ of the stearic acid and ½ of the magnesiumstearate are passed through a mill and added to a blender equipped withan intensifier bar. The mixture is blended for approximately twentyminutes with the intensifier bar on and then chilsonated and milled. Theremaining ProSolv SMCC90, and stearic acid are added and mixed foranother 10 minutes. The remaining magnesium stearate is screened andadded to the blender with the granulation. The blend is mixed forapproximately 3 minutes with the intensifier bar off. The blend iscompressed into tablets using a suitable tablet press.

Example V Enteric-Coated Tablets Containing Risedronate and EDTA

Enteric-coated tablets containing risedronate and EDTA are made bypreparing a coating composition and compressed tablets containingrisedronate and EDTA, and then applying said coating composition to saidtablets.

An enteric coating composition is prepared in the form of a lacquercontaining the following excipients, per tablet:

A. Enteric Coating Suspension

Ingredients: Eudragit L 30 D-55 ® (wet basis) 150 mg  (manufactured byRöhm Pharma GmbH and Co. KG, Darmstadt, Germany) Triethylcitrate 10 mgTalc 30 mg Black Iron Oxide 0.1 mg  Purified Water 250 mg 

The enteric coating is prepared using the following method:

The talc and black iron oxide are added to a portion of purified waterand mixed until uniform. The triethylcitrate is added with continuousmixing. The resulting pigment suspension is next passed through a screenor a suitable mill to break up agglomerates. The Eudragit L 30 D-55® isscreened and then added to a suitable vessel and diluted with a portionof the purified water. The pigment suspension is then added to thediluted Eudragit suspension and mixed until uniform.

In a suitable coating pan, the compressed tablets (10 kg) containingrisedronate and EDTA, described below, are warmed to about 30-35° C. Theenteric coating suspension is sprayed onto the tablets at approximately30 grams per minute. When the spray cycle is completed, the temperatureis reduced and the tablets are removed and dried at 30-35° C. forapproximately 1 hour.

A coating weight gain of 35% (total solids) is applied by spraying theabove composition onto compressed tablets containing risedronate andEDTA, prepared in Part B below.

B. Compressed Tablets Containing Risedronate and EDTA

The enteric coating suspension prepared in Part A above is sprayed onto5 mg risedronate tablets, each tablet weighing 240 mg and eachcontaining:

Active Ingredients: Risedronate sodium   5.0 mg* Chelant: Disodium EDTA 75.0 mg Excipients Microcrystalline cellulose 149.5 mg Sodium starchglycolate    9 mg Stearic acid  1.5 mg *This amount is calculated on arisedronate anhydrous monosodium salt basis.

Tablets having the composition set forth above are prepared as follows:

The tablets are prepared by sieving the risedronate active ingredientand the EDTA with ½ of the microcrystalline cellulose into a twin shellblender. The blend is then mixed until uniform. Then, ½ of the stearicacid is added and the blend is mixed further. The blend is then isroller compacted and milled. The remaining microcrystalline celluloseand sodium starch glycolate are added and mixed until uniform. Theremaining stearic acid is then added and mixed until adequatelubrication is achieved. Tablets are then compressed on a rotary tabletpress.

Example VI Time Dependent and Enteric Coated Tablets ContainingRisedronate and Sodium Citrate

Time Dependent and Enteric Tablets containing risedronate and sodiumcitrate are made by preparing a two layer coating composition andcompressed tablets containing risedronate and sodium citrate and thenapplying said coating composition to said tablets.

The first layer (Time Dependent Coating Layer) coating composition isprepared in the form of a polymer containing the following excipients,per tablet:

A. Acid Soluble Coating Layer

Ingredients: Ethylcellulose 40.0 mg Dibuty Sebacate   8 mg Toluene  250mg Ethyl Alcoholc   70 mg

The acid soluble coating is prepared using the following method:

A solution is prepared by adding the ethylcellulose to approximatelytwo-thirds of the toluene:ethyl alcohol mixture while mixing. Thesolution is mixed for at least two hours. The dibuty sebacate is addedand mixed for an additional two hours. The resulting coating solution isscreened and mixed throughout the coating process.

B. Enteric Coating Suspension

Ingredients: Eudragit L 30 D-55 ® (wet basis)  150 mg (manufactured byRöhm Pharma GmbHand Co. KG, Darmstadt, Germany) Triethyl citrate  6.0 mgTalc 15.0 mg Red Iron Oxide 0.25 mg Purified Water  260 mg

The enteric coating is prepared using the following method:

A pigment suspension is prepared by adding ground ferric oxide, and talcto approximately two-thirds of the purified water while mixing. Thesuspension is mixed for at least two hours. The Eudragit L 30 D-55solution and triethyl citrate are combined and mixed for at least 45minutes. The pigment suspension is then added to the Eudragit solutionand mixed for 30 to 60 minutes. The resulting coating suspension isscreened and mixed throughout the coating process.

The compressed tablets are transferred to the coating pan and preheatedwith occasional jogging. The compressed tablets are coated with the TimeDependent Coating then with the Enteric Coating Suspension using atypical pan coating process until the required quantity of coatingsolution has been applied. Tablets are then cooled and collected insuitable containers.

A coating weight gain of 10% for the Time Dependent Coating and 13%Enteric Coating (total solids compared to that of the core tabletweight) is applied by spraying the above composition (A and B) ontocompressed tablets containing risedronate and sodium citrate prepared inPart C below.

C. Compressed Tablets Containing Risedronate and Sodium Citrate

The Acid Soluble Coating and the Enteric Coating suspension prepared inPart A and B above is sprayed onto 5 mg risedronate tablets, each tabletweighing 500 mg and each containing:

Active Ingredients: Risedronate Sodium    5 mg* Chelant: Sodium Citrate  250 mg Excipient Microcrystalline Cellulose 109.5 mg CroscarmelloseSodium  25.0 mg Mannitol   100 mg Magnesium stearate  0.5 mgPolyvinylpyrrolidone   10 mg Purified Water 100.0 mg *This amount iscalculated on a risedronate anhydrous monosodium salt basis.

Tablets having the composition set forth above are prepared as follows:

The risedronate sodium, sodium citrate, microcrystalline cellulose,croscarmellose sodium, mannitol and polyvinylpyrrolidone are passedthrough a mill and added to a blender equipped with an intensifier bar.The mixture is blended for approximately ten minutes with theintensifier bar on and granulated with purified water for 15 minutes.The mixture is dried overnight at 30° C., passed through a mill. Themagnesium stearate is screened and added to the blender. The blend ismixed for approximately 3 minutes with the intensifier bar off. Theblend is compressed into tablets using a suitable tablet press.

Example VII Time Dependent Delivery Tablets Containing Risedronate andEDTA

Time dependent delivery tablets containing risedronate and EDTA are madeby preparing a coating composition and compressed tablets containingrisedronate and EDTA, and then applying said coating composition to saidtablets.

A coating composition is prepared containing the following excipients,per tablet:

A. Coating Suspension

Excipients: Carnauba Wax 80 mg Beeswax 35 mg Polyoxyethylene sorbitanmonooleate 11 mg Hydroxypropylmethylcellulose 24 mg Purified Water 500mL

The coating is prepared using the following method:

The carnauba wax, beeswax, polyoxyethlyene sorbitan monooleate, andhydroxypropylmethylcellulose are added to the purified water at 60° C.and mixed for 3 hours. The resulting coating mixture is screened andmixed throughout the coating process. The core tablets are transferredto the coating pan and preheated with occasional jogging. Tablets arecoated, using a typical pan coating process until the required quantityof coating solution (at 60° C.) has been applied. Tablets are thencooled and collected in suitable containers.

A coating weight gain of 30% (total solids) is applied by spraying theabove composition onto compressed tablets containing risedronate andEDTA, prepared in Part B below.

B. Compressed Tablets Containing Risedronate and EDTA

The coating suspension prepared in Part A above is sprayed onto 35 mgrisedronate tablets, each tablet weighing 500 mg and each containing:

Active Ingredients: Risedronate Sodium  35 mg* Chelant: Disodium EDTA150 mg Excipients: Microcrystalline cellulose  50 mg Spray Dried Lactose245 mg Sodium starch glycolate  15 mg Magnesium stearate  5 mg *Thisamount is calculated on a risedronate anhydrous monosodium salt basis.

Tablets having the composition set forth above are prepared as follows:

The risedronate sodium, EDTA disodium, microcrystalline cellulose, Spraydried lactose and sodium starch glycolate are passed through a mill andadded to a blender equipped with an intensifier bar. The mixture isblended for approximately ten minutes with the intensifier bar on. Themagnesium stearate is screened and added to the blender. The blend ismixed for approximately 3 minutes with the intensifier bar off. Theblend is compressed into tablets using a suitable tablet press.

Example VIII Enteric-Coated Tablets Containing Risedronate and EDTA

Enteric-coated tablets containing risedronate and EDTA are made bypreparing a coating composition and compressed tablets containingrisedronate and EDTA, and then applying said coating composition to saidtablets.

An enteric coating composition is prepared in the form of a lacquercontaining the following excipients, per tablet:

A. Enteric Coating Suspension

Ingredients: Eudragit L 30 D-55 ® (wet basis) 47.8 mg (manufactured byRöhm Pharma GmbH and Co. KG, Darmstadt, Germany) Triethylcitrate 2.15 mgTalc 7.17 mg Red Iron Oxide 0.07 mg Simethicone emulsion (30%) 0.14 mgPolysorbate 80 0.14 mg Purified Water 102.6 mg 

The enteric coating is prepared using the following method:

A pigment suspension is prepared by adding polysorbate 80, ground ferricoxide, and talc to approximately two-thirds of the purified water whilemixing. The suspension is mixed for at least two hours. The 30%simethicone emulsion and the remaining water are added to the pigmentsuspension and mixed for at least 45 minutes. The Eudragit L30 D-55®solution and triethyl citrate are combined and mixed for at least 45minutes. The pigment suspension is then added to the Eudragit solutionand mixed for 30 to 60 minutes. The resulting coating suspension isscreened and mixed throughout the coating process. The core tablets aretransferred to the coating pan and preheated with occasional jogging.Tablets are coated, using a typical pan coating process until therequired quantity of coating solution has been applied. Tablets are thencooled and collected in suitable containers.

The enteric coating suspension prepared in Part A above is sprayed onto35 mg risedronate tablets, each tablet weighing 240 mg and prepared asin Example IB

Example IX Enteric-Coated Soft Gelatin Capsules Containing Risedronateand Disodium EDTA

Enteric-coated capsules containing risedronate and EDTA are made bypreparing a coating composition and soft gelatin capsules containingrisedronate and EDTA, and then applying said coating composition to saidsoft gelatin capsules.

An enteric coating composition is prepared in the form of a lacquercontaining the following excipients, per tablet:

A. Enteric Coating Suspension

Excipients: Eudragit L 30 D-55 ® (wet basis) 200.0 mg  (manufactured byRöhm Pharma GmbHand Co. KG, Darmstadt, Germany) Dibutyl phthalate 10.0mg Talc 30.0 mg Red Iron Oxide 0.25 mg Simethicone emulsion (30%) 0.50mg Polysorbate 80 0.50 mg Purified Water  350 mg

The enteric coating is prepared using the following method:

A pigment suspension is prepared by adding polysorbate 80, ground ferricoxide, and talc to approximately two-thirds of the purified water whilemixing. The suspension is mixed for at least two hours. The 30%simethicone emulsion and the remaining water are added to the pigmentsuspension and mixed for at least 45 minutes. The Eudragit L 30 D-55solution and dibutylphthalate are combined and mixed for at least 45minutes. The pigment suspension is then added to the Eudragit solutionand mixed for 30 to 60 minutes. The resulting coating suspension isscreened and mixed throughout the coating process. The soft gelatincapsules are transferred to the coating pan and preheated withoccasional jogging. The soft gelatin capsules are coated, using atypical pan coating process until the required quantity of coatingsolution has been applied. Capsules are then cooled and collected insuitable containers.

A coating weight gain of 13% (total solids) is applied by spraying theabove composition onto soft gelatin capsules containing risedronate andEDTA, prepared in Part B below.

B. Soft Gelating Capsules Containing Risedronate and EDTA

The enteric coating suspension prepared in Part A above is sprayed onto50 mg risedronate soft gelatin capsules, each weighing 764 mg and eachcontaining:

Fill Composition Risedronate sodium   50 mg* Oleoyl Macrogol-6Glycerides  370 mg Colloidal Silicon Dioxide   5 mg Disodium EDTA  125mg Total  550 mg Gel Shell Composition Gelatin 123.4 mg  Glycerin 44.1mg Anhydrized Liquid Sorbitol (Sorbitol Special, 27.1 mg 76%) PurifiedWater 17.1 mg Titanium dioxide  1.0 mg FD&C Red No. 40, E129 0.96 mgFD&C Blue No. 1, E133 0.30 mg Total  214 mg Total Capsule weight  764 mg*This amount is calculated on a risedronate anhydrous monosodium saltbasis.

Soft gelatin capsules having the composition set forth above areprepared as follows:

The Oleoyl Macrogol-6 Glycerides is added to a suspension tank equippedwith an overhead mixer. The risedronate sodium, disodium EDTA, colloidalsilicon dioxide are passed through a mill and added to the OleoylMacrogol-6 Glycerides with continued mixing. The mixture is blended forapproximately 60 minutes. The blend is then deaerated and ready forfilling into capsules. With mixing, the glycerin, sorbitol special, andpurified water are combined in a heated vacuum vessel. Heat is applieduntil the temperature reaches at least 80° C., then the gelatin is addedand mixed for 75 minutes. The gel mass is examined for completedissolution of particles. If needed, continued heating and mixing isapplied until there is no visual evidence of undissolved particles. Thegel mass is deaerated, then the titanium dioxide, FD&C Red No. 40 andFD&C Blue No. 1 are added with continued mixing. The gel mass isdischarged into heated gel holding tanks for subsequent processing. Thefill material is then encapsulated on a soft gelatin capsule filler.

Example X

A 65 kg woman diagnosed with postmenopausal osteoporosis is prescribedthe enteric-coated oral dosage form of Example I, to be taken onceweekly, comprising 35 mg risedronate and 100 mg Disodium EDTA. Thepatient takes the oral dosage form with breakfast once per week. Theamount of risedronate absorbed is equivalent to that of a 35 mgimmediate released tablet taken in a fasted state.

Example XI

A 70 kg man diagnosed with prostate cancer and high bone turnover isprescribed the enteric-coated oral dosage form of Example I, to be takenonce weekly, comprising 35 mg risedronate and 150 mg citric acid. Thepatient takes the oral dosage form once per week, immediately beforegoing to sleep. The patient does not experience upper GI irritation ordiscomfort.

Example XII

A group of women diagnosed with postmenopausal osteoporosis areprescribed the enteric-coated oral dosage form of Example IV comprising50 mg risedronate, to be taken once weekly. The patients take the oraldosage form with breakfast once per week. The amount of risedronateabsorbed is equivalent to that of a 35 mg immediate released tablettaken per label, at 30 minutes before food or drink.

All documents cited are, in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present invention.

While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this invention.

1. An oral dosage form having pharmaceutically effective absorptioncomprising: (a) from about about 1 mg to about 250 mg of abisphosphonate selected from the group consisting of risedronate andacids, salts, and esters thereof; (b) from about 10 mg to about 500 mgof EDTA; and (c) a delayed release mechanism to immediately release therisedronate and the EDTA in the small intestine; wherein saidcomposition weighs no greater than 1 gram.
 2. The oral dosage form ofclaim 1 wherein the EDTA is disodium EDTA.
 3. The oral dosage form ofclaim 1 wherein the delayed release mechanism is selected from the groupconsisting of pH triggered delivery systems, time dependent deliverysystems and mixtures thereof.
 4. The oral dosage form of claim 3 whereinthe delayed release mechanism is a pH triggered delivery system.
 5. Theoral dosage form of claim 4 wherein the pH triggered delivery systemcomprises an enteric coating.
 6. The oral dosage form of claim 5 whereinthe enteric coating disintegrates between about pH 5.5 and about pH 6.5.7. The oral dosage of claim 5 which comprises from about 75 mg to about250 mg of EDTA, wherein the EDTA is disodium EDTA.
 8. An oral dosageform having pharmaceutically effective absorption comprising: (a) fromabout 1 mg to about 250 mg risedronate sodium; (b) from about 25 mg toabout 500 mg of disodium EDTA; and (c) an enteric coating which providesfor immediate release of the risedronate sodium and the disodium EDTA inthe small intestine of a mammal.
 9. The oral dosage form of claim 8comprising from about 35 mg to about 50 mg of the risedronate sodium.10. A method for treating a disease selected from the group consistingof osteoporosis, Paget's disease, hyperparathyroidism, hypercalcemia ofmalignancy, osteolytic bone metastasis, and combinations thereof,comprising administering to a human or other mammal in need thereof asafe and effective amount of the oral dosage form of claim
 1. 11. Themethod of claim 10 wherein the disease is osteoporosis.
 12. The methodof claim 11 wherein the oral dosage form is administered according to acontinuous schedule having a dosing interval selected from the groupconsisting of daily, weekly, three times per month, twice monthly, andonce monthly.
 13. The method of claim 12 wherein the oral dosage form isadministered weekly.
 14. The method of claim 10 wherein the oral dosageform is administered with or without food.
 15. The oral dosage form ofclaim 8 comprising from about 15 mg to about 55 mg of the risedronatesodium.
 16. The oral dosage form of claim 15 comprising from about 75 mgto about 250 mg of the disodium EDTA.
 17. The oral dosage form of claim16 comprising about 35 mg of the risedronate sodium.
 18. The oral dosageform of claim 17 wherein the enteric coating is a methacrylic acidcopolymer.
 19. The oral dosage form of claim 17 comprising about 100 mgof the disodium EDTA.
 20. The oral dosage form of claim 19 wherein theenteric coating is a methacrylic acid copolymer.
 21. The oral dosageform of claim 8 comprising from about 50 mg to about 280 mg of therisedronate sodium.
 22. The oral dosage form of claim 21 comprising fromabout 75 mg to about 250 mg of the disodium EDTA.
 23. The oral dosageform of claim 22 comprising about 150 mg of the risedronate sodium. 24.The oral dosage form of claim 23 wherein the enteric coating is amethacrylic acid copolymer.
 25. The oral dosage form of claim 23comprising about 100 mg of the disodium EDTA.
 26. The oral dosage formof claim 25 wherein the enteric coating is a methacrylic acid copolymer.27. A method for treating osteoporosis comprising administering to ahuman or other mammal in need thereof a safe and effective amount of theoral dosage form of claim
 17. 28. The method of claim 27 wherein theoral dosage form is administered with or without food.
 29. A method fortreating osteoporosis comprising administering to a human or othermammal in need thereof a safe and effective amount of the oral dosageform of claim
 25. 30. The method of claim 29 wherein the oral dosageform is administered with or without food.